4 adamantylamino quinolines

ABSTRACT

A group of novel 4-(adamantylamino)quinoline compounds which are useful as algaecides and protozoacides. Some are useful as anti malarias.

taies flew 1 German [451 May 1,1973

[ 4 ADAMKNTVLKMIWO QUINOLINES [75] Inventor: Koert Gerzon, Indianapolis, Ind.

[73] Assignee: Eli LiIIy and Company, Indianopolis, Ind.

[22] Filed: Nov. 26, 1971 [21] Appl. No.: 202,571

[56] 4 References Cited UNITED STATES PATENTS 3,310,469 3/1967 Paulshock et al. 424/258 3,322,752 5/1967 Bernstein ..260/268 PC 3,391,142 7/1968 Mills et a] ..260/283 QTHER PUBLICATIONS Narayanan et a1. Chem. Abstr. Vol. 75, C01. 35804 Abstr. German 2,050,074

Primary Examiner-Dona1d G; Daus Att0rneyEveret F. Smith et a1.

[5 7 ABSTRACT A group of novel 4-(adamantylamino)quinoline compounds which are useful as algaecides and protozoacides. Some are useful as anti malarias.

9 Claims, No Drawings 1 ADAMANTYLAMINOQUINOLINES SUMMARY OF THE INVENTION The present invention is directed to compounds of the following formula:

useful not only in isolating the compounds, but also in formulating the compounds for other uses. Typically, mono-acid addition salts are formed; but the compounds of Formula I contain multiple sites for acid-ad- 5 dition salt formation and all salts, regardless of stoichiometric proportions, are within the scope of the 5 l present invention. The identity of the acid salt-forming 6 3 moiety is not critical, although a given anion may in i some instances exhibit special advantages, such as I I 1o ready solubility, ease of crystallization, and the like. I Representative and suitable acids include the followwherein R is located at either the 6- or 7-position and mg: hydrochloric, f p hydfoiodic Sulfuric represents tartaric, phosphoric, nitrlc, and the like. In some em- 1 halo of an atomic weightless than 85 or bodiments a pharmaceutically-acceptable acid-addilloweralkoxy; tion salt is preferred. Pharmaceutically-acceptable" and wherein 1 represents salts are those saltsformed from acids which do not inwhen R is at the @Poshion crease the toxicity of the compound as a while toward Ladam amylamino or warm-blooded animals. b. Z-adamantylamino; or, Synthesis 2 when R is at the 7 i i Generally, the free base compounds of the present a, 1 adamamy1amino invention are prepared by a simple condensation reacb Ladamanwlamino, tion illustrated bythe following reaction seqge ce: c. 3,5,7-tri (R )-l-adam,antyla mino wherein each R f independently represents Phenol 1. hydrogen, R il w HR! R i 2. methyl, or

subject to the limitation that all R groups together This condensation reaction between the appropriate 4- m i f one to fi b th i l i carbon halo-6- or 7 substituted quinoline derivative and the atoms; or corresponding 1- or Z-adamantylamine derivative (HR (1. a 3-substituted-l-adamantylamino wherein the is conducted in the presence of phenol as a solvent substituent at position 3 is and a catalytic amount of sodium iodide. The reaction 1. carboxyl, proceeds over a range of reaction temperatures, such 2. loweralkoxycarbonyl, as from 80 to 200 C., but is preferably conducted at 3. carbamoyl, reflux temperatures. The optimum length of reaction 4-l0weralkylcarbam0yl, varies from refluxing about ten hours to about 100 5. diloweralkylcarbamoyl, hours, depending upon the reactants used. Separation aminomethyl, and, if desired, purification are accomplished by 7. loweralkylaminornethyl, or established procedures.

diloweralkylaminomethyl; Some of the compounds of Formula I are not readily the moieties loweralkyp designating alkyl and alkoxy prepared by the foregoing general method. These are radicals of from one to three, both inclusive, carbon the compounds wherein R represents a 3-substitutedatoms; and the acidaddition Salts thereofl-adamantylamino derivative wherein the 3-substituent The compounds defined above are useful as is carboxyl, carbamoyl, loweralkylcarbamoyl, protozoacidal and algaecidal agents. In addition, cerdiloweralkylcarbamoyl, aminomethyl lowerah of the foregomg PP of Formula I are kylaminomethyl, or diloweralkylaminomethyl. These ful m the treatment ofmalana compounds are prepared in a further reaction DETAILED DESCRIPTION OF THE INVENTION- Sequence, as follows:

COMPOUNDS The scope of compounds in accordance with the present invention is as defined hereinabove. In those -UO0Alkyl 410011 moieties defined herein as loweralkyl and loweralkoxy, the alkyl portion can be straight or branched chain. Bus 1 NH H N In those R substituents which contain dlloweralkylcarbamoyl or diloweralkylamino groups, the alkyl NW groups can be alike or different. l m Nucleophilie The acid-addition salts of the com ounds of Formula R- chlofid I are included within the scope of this invention and are \Ny 41001 041mm ClI:NR- R Nlllt lt I l (lll(.l.lt)ll N 1 I *M' w T l l R li -11 0r loweralkyl The starting ester in this reaction sequence can be prepared by the foregoing general method. This ester is cleaved by heating with strong base, sodium hydroxide for example, in a suitable solvent such as aqueous ethanol. The corresponding acid chloride is prepared by refluxing the acid thus formed with a nucleophilicchloride-supplying reagent such as oxalyl chloride for several hours. Reaction of the resulting acid chloride with an excess of an appropriate amine yields the corresponding amide derivative. The amide derivative thus obtained can be reduced with an agent such as lithium aluminum hydride to give the desired amine product.

The compounds of Formula 1 form acid-addition salts. These salts are prepared using conventional procedures by reacting a free base of Formula 1 with the appropriate acid. Separation and, if desired, purification are accomplished by established procedures.

The following examples illustrate the synthesis of representative compounds of the present invention.

EXAMPLE 1 7-Chloro-4-(3,5,7-trimethyl-l-adamantylamino)quinoline Hydrochloride 3,5,7-Trimethyladamantylamine hydrochloride g.), prepared by the method of Gerzon, et al., J. Med. Chem 10, 603 (1967), was dissolved in hot water. A small amount of concentrated sodium hydroxide (less than 5 ml.) was added, and the resulting solution was extracted with ethyl acetate. The ethyl acetate solution was washed once with water, was dried over anhydrous sodium sulfate, was filtered and concentrated under vacuum to a small volume. 4,7-Dichlor0quinoline (4.35 g.), phenol (6 g.), and sodium iodide mg.) were added to the 3,5,7-trimethyladamantylamine thus prepared. The reaction mixture was heated (180 C.) and stirred for 20 hours. At this point 100 ml. of 35 percent sodium hydroxide solution was added. The resulting solution was allowed to stand overnight and then was extracted twice with diethyl ether and once with ethyl acetate. These organic extracts were washed with water, dried over anhydrous sodium sulfate, were filtered and evaporated under vacuum. The residue obtained was dissolved in methanol; HCl gas was introduced, forming a precipitate which was filtered, washed with water, and filtered again. The precipitate was then crystallized from methanol to give 2.1 g. of 7- chloro-4-(3,5,7-trimethyl-l-adamantylamino)quinoline hydrochloride, m.p. above 300 C. Analysis calculated for C H CI N Theory: C, 67.51; H, 7.21; N, 7.16

Found: C, 67.26; H, 7.35; N, 6.93

EXAMPLE 2 evaporated under vacuum to give a dark oil. The

hydrochloride salt was prepared by dissolving the oil in diethyl ether and bubbling HCl gas through the ethereal solution. The precipitate formed was separated by filtration and was recrystallized from an absolute ethanol-hexane solvent mixture to give 4.7 g. of 7-chloro-4-(3-ethoxycarbonyl-l-adamantylamino)quinoline hydrochloride, m.p. 204206 C. Analysis calculated for C H Cl N O z Theory: C, 62.49; H, 6.6; Cl, 16.5; N, 6.82

Found: C, 61.91; H, 6.6; C1, 16.5; N, 6.65

EXAMPLE 3 4-(3-Carboxy-l-adamantylamino)-7-chloroquinoline Hydrochloride Two grams of 7-chloro-4-(3-ethoxycarbonyl-l-adamantylamino)quinoline hydrochloride, 30 ml. of 1 N sodium hydroxide solution, and 15 ml. of absolute ethanol were stirred and heated under reflux for one and one-half hours and then stirred overnight at room temperature. The resulting solution was evaporated to dryness under vacuum. The residue thus obtained was taken into water, and the aqueous solution was adjusted to a neutral pH by addition of dilute hydrochloric acid. The white solids formed were separated, triturated with absolute ethanol and converted to the hydrochloride salt by the further addition of hydrochloric acid. The solid material formed was separated to give 4-(3-carboxy-l-adamantylamino)-7-chloroquinoline hydrochloride, m.p. 250 C. Elemental analysis calculated for C H Cl N O Theory: C, 61.07; H, 5.63; N, 7.12;

Found: C, 61.03; H, 5.65; N, 7.04.

EXAMPLE 4 7-Chloro-4-(3-chloroformyl-1-adamantylamino)quinoline Hydrochloride A suspension of 4-(3-carboxy-1-adamantylamino)-7- chloroquinoline (2 g.) in dry benzene to ml.) was stirred rapidly at room temperature during the addition of oxalyl chloride (25 ml.). The resulting reaction mixture was heated under reflux for about three hours, then cooled and evaporated to dryness in vacuo. The residue was dissolved in dry benzene and reevaporated in vacuo two times. The material thus obtained was used directly to prepare the compound of Example 5.

EXAMPLE 5 7-Chloro-4-[3-(N,N-diethylcarbamoyl)-l-adamantylaminolquinoline Hydrochloride An excess of diethylamine (45 ml.) was added dropwise to a chilled suspension of 7-chloro-4-(3-chloroformyl-l-adamantylamino)-quinoline hydrochloride (approximately 2 g.) in dry benzene ml.), stirring constantly. The resulting mixture was stirred overnight at room temperature. The solids still present were separated by filtration and then were dissolved as much as possible in additional benzene. This benzene solution was combined with the reaction solution, and the resulting solution was evaporated to dryness under vacuum to give 2.3 g. of 7-chloro-4-[3-(N,N-diethylcarbamoyl)- l -adamantylaminolquinoline. The hydrochloride salt was prepared, m.p. 360-364 C. Analysis calculated for c n cl n oz Theory: C, 65.38; H, 7.65; N, 9.63

Found: C, 64.28; H, 6.97; N, 9.37

EXAMPLE6 7-Chloro-4-l3-(N,N-diethylaminomethyl)-l-adamantylaminoIquinoline Hydrochloride A solution of 7-chloro-4-[3-(N,N-diethylcarbamoyl)-l-adamantylamino]quinoline (2 g.) in dry tetrahydrofuran (100 ml.) was added dropwise to a suspension of lithium aluminum hydride (0.5 g.) in dry tetrahydrofuran (50 ml.). The resulting mixture was stirred at room temperature for 1 hour, then was heated under reflux for about 6 hours, and subsequently was stirred overnight at room temperature. The mixture was then stirred and cooled in an ice bath during the dropwise addition first of 100 ml. ofa 5 percent solution of aqueous tetrahydrofuran and then of about 3 ml. of 5 N sodium hydroxide solution. The precipitate containing aluminum salts was separated by filtration, and the filtrate was evaporated under vacuum to give an oil. This oil was dissolved in tetrahydrofuran and re-evaporated two times; the residue was then dissolved in diethyl ether and was dried over anhydrous sodium sulfate. The ethereal solution was filtered and evaporated under vacuum. The residue was again dissolved in diethyl ether; HCl gas was bubbled into this solution; and the precipitate formed was separated to obtain the hydrochloride salt of 7-chloro-4- 3-( N ,N-diethylaminomethyl 1 -adamantylamino]quinoline, m.p. 140 (d).

Analysis calculated for C H ClN /2 HO Theory: C, 62.3; H, 7.64; N, 9.09; Cl, 19.15 Found: C, 61.91; H, 8.20; N, 7.52; Cl, 18.90

EXAMPLES 7-19 Other representative compounds of Formula 1 prepared using the methods described with analogous starting materials and exemplified hereinabove include: 4-( 1-adamantylamino)-7-chloroquinoline hydrochloride, prepared from 4,7-dichloroquinoline and l-aminoadamantane by the method of Example 1, m.p. 266-268 C. 4-(3,5-diethyl-l-adamantylamino)7-methoxyquinoline hydrochloride, prepared from 4-chloro-7- methoxyquinoline and l-amino-3,S-diethyladamantane by the method of Example 1. 4-(1-adamantylarnino)-7-propoxyquinoline, prepared from 4-chloro-7-propoxyquinoline and l-aminoadamantane by the method of Example 1. 4-(Z-adamantylamino)-7-chloroquinoline hydrochloride, prepared from 4,7-dichloroquinoline and 2aminoadamantane by the method of Example 1, m.p. 238239 C. 7-chloro-4-( 3-methoxycarbonyll -adaman tylamino)quinoline hydrochloride, prepared from 4,7- dichloroquinoline and methyl 3-aminoadamantane-learboxylate by the method of Example 2.

4-( 2-adam antylamino )-6-chloroquinoline, prepared from 4,6-dichloroquinoline and 2-aminoadamantane by the method of Example 1. 4-(l-adamantylamino)-6-methoxyquinoline, prepared from 4-chloro-6-methoxyquinoline and l-aminoadamantane by the method of Example 1, m.p. 247-248 C.

4-( 1-adamantylamino)-7-bromoquinoline hydrobromide, prepared from 4,7dibromoquinoline and 1 aminoadamantane by the method of Example 1.

4( 3-carbamoyll -adamantylamino )-7-chloroquinoline, prepared from 7-chloro-4-( 3-chloroformyl-ladamantylamino)quinoline and ammonia by the method of Example 5. 4-(3-aminomethyl-1-adamantylamino)-7-chloroquinoline hydrochloride, prepared by reduction of 4-(3-earbamoyl-l-adamantylamino)-7-chloroquinoline by the method of Example 6.

6 7-ethoxy-4-(3 methyl1-adamantylamino)quinoline, prepared from 4-chloro-7-ethoxyquinoline and lamino-3-methy1adamantane by the method of Example 1.

7-chloro-4-[ 3-( N-isopropylcarbarnoyl 1 -adamantylamino]quinoline, prepared from 7-chloro-4-(3- chloroformyl-1-adamantylamino)-quinoline and isopropylamine by the method of Example 5. 7-chloro-4-[3-(N-isopropylamino)-1-adarnantylamino ]quinoline hydrochloride, prepared by reduction of 7- chloro-4-[ 3-( Nisopropylcarbamoyl l -adamantylamino]quinoline by the method of Example 6.

DETAILED DESCRIPTION OF THE INVENTION- UTILITY It has been discovered that compounds of Formula I are adapted to be employed for the control of protozoan and algal organisms. This activity of the compounds can be utilized in any of a number of applications.

In one embodiment the compounds of the present invention can be used as agents to control the growth of algal and/or protozoan organisms in vitro, such as in water bodies and other locations suited to the growth of algae and protozoa. Control of algal and/or protozoan organisms can be accomplished by the addition of an effective amount of a Formula I compound to, for example, the water body. Typically, the compounds are effective at concentrations of from 50 to 1,000 parts per million or more.

In another embodiment, the compounds of the present invention can be used to control or prevent diseases caused by protozoan parasites which attack various warm-blooded animals.

In a particularly preferred aspect of this embodiment, 4-( 1-adamantylamino)-7-chloroquino1ine hydrochloride and 7-chloro-4-(3,5,7-trimethyl-l-adamantylamino)quinoline hydrochloride are utilized for control and prevention of those specific Plasmodium protozoan agents which cause malaria. The administration of these compounds can be oral or parenteral. Oral administration may be by direct ingestion of the drug, or by admixture of the active agent with the food or water supply of the warm-blooded animals to be treated. Although the dose should, in every case, be individualized, in view of the species, age, weight, the Plasmodium strain involved, and the severity of the malarial infection, the compounds of the present invention typically are effective in the control of Plasmodium when administered in dosages from 25 to 60 mg./kg. of body weight of warm-blooded animal; doses can be divided for convenient administration.

In all the above embodiments of this invention the compounds of Formula I can be used as either the free base or in a physiologically-acceptable acid-addition salt form. When administered to animals, the compounds can be administered alone or together with a suitable carrier or carriers. The active agents can be administered in the form of tablets, capsules, injections and in liquid or powder form. In the instance of the first embodiment, application can consist of spraying a body of water with a liquid or powder formulation incorporating an agent of Formula I with surface-active dispersing agents such as non-ionic emulsifying agents.

The following examples are illustrative of the usefulness of the compounds of Formula 1 for the control of protozoa and algae and will enable those skilled in the art to practice the same.

EXAMPLES 20-25 The compounds are suspended in sesame or peanut protozoamAlgae Screening procedure oil. The resulting suspension is administered to the Discs of highly absorbent paper, 635 m i di animals to be treated in a single subcutaneous dose, 72 lcr are i d i a l i f h test compound in hours after infection with Plasmadium berghei. At this water, water-ethanol (lzl water-acetone-ethanol time a m Pcrcem Parasimmia has developed; the (1;1;1) or water-ethano]-acetone-dimethylformamide disease is well established but has not produced suffi- (1;1;1;|) as i necessary fo l bili to b i a cient debility to alter the response of the host to toxic centration of 40 micrograms of test compounds per effects Of thfi drug on 6511. In order to check fHCIOI'S such as changes in the infectivity of the Plasmodium berghei or in the susceptibility of the host or to detect disc. Agar plates are prepared using a medium appropriate for the growth of the desired test organism 10 and introducing sufficient serum by pipette to secure 3 technical errors, a group of infected animals treated million organisms per ml. of agar. The treated discs are With py methamine at d se levels producing definite placed on agar plates corresponding to the test organincreases in survival time is included as a positive conisms. After 24 hours for Tetrahymena pyrzformis, and 1- after 48 hours for Ochromonas malhamensis, Chlorella Test compounds are administered in graded dosages. vulgaris, and Scenedesmus basiliensis, the observable If deaths occur in test animals prior to the 6th day, zones of inhibition are measured. Results are rated on when untreated controls die, these are regarded as nonthe basis of one for observable zones under 25 mm. in parasitic; this is the basis for toxicity evaluation. The diameter or two -H- for zones over 25mm. in diameter. 20 mean survival time of treated animals is calculated in The following results were observed in tests of comdays, based on the survival times of all animals receivpounds of Formula I using this procedure. Organisms ing chemical therapy. The mean survival time of connamed were inhibited with a one rating; a two in trols in days is based on the survival times ofall control parenthesis indicates two -ll-inhibition. animals. The mean control-survival time is subtracted TABLE 1 Compound Inhibition of protozoa Inhibition of algae 4-(1-adn1anantylmnino)-7-chloroquinoline hydrochloride I i hlorzlla truly art's. -l-(2-ad:imantlylnmhi0)-7-chloroquin0linc hydrochloride g fgflggu'f if g ig fg ggg T- :hloro-4(3-vthoxymrhonyll-adaniantylamino) quinolinc hydrochloride ..{2223355 221; zgz fgxgi t:Ii::}SC(II1JI1E8THU$ busz'lincnsis. 7chl0ro--t-l3-(N,N- Iiothylcarbamoyl)-1-admantylamin0] quinolinv hydrochloride 'l' 'lmhymnm pyriformis Scmcdmmus baxilicnsis. T-chlm-o-4-[3-(N.N-diethylaminoniethyl)-1adamantylmnino] quinolinthydrochlorido Tdmhwm "a pun-form ighlzrfjllangglgbaglrii "sis l-LHrdamnntyltmlino)6-methoxyquinoline Ochronmnas malhamcnsis cii lofnl liz vuigaris. c i

The following examples illustrate the use of from the mean survival time of treated animals to give representative compounds of Formula I for the control change in survival time. An increase in survival time of of malaria and will enable those skilled in the art to two or more days is considered significant. practice the same. In tests using this procedure, wherein the mean control survival time was 6.1 days, the compounds of For- EXAMPLES 26'27 mula II increased survival times as follows:

Antimalarial Screening Procedure All The rodent antimalarial test, as conducted by the Walter Reed Army Institute of Research, Walter Reed Army Medical Center, is based on comparisons of M responses by mice infected with Plasmadium berghei KBG I73 malaria to test compounds. The results are H expressed in mean survival times of treated animals as compared with mean survival times of untreated controls. Young non-inbred [CR/HA Swiss mice and standard inoculum of Plasmodium berghei KBG 173 are C!" used to produce a uniform disease fatal to 100 percent of untreated animals within 6 to 8 days, with a mean TABLEZ survival time of 6.1 days. Test animals weigh from 18 to 22 grams, but weight variations in any given experi- 2 33;? Mean survivalTimc mental group are confined to two to three grams. All ousumgykg) 20 animals in any test are approximately the same age. 40 Tmic 30 I 320 640 Animals on test are housed in metal-topped plastic Deaths cages and are given a standard laboratory diet and 60 Run 10 water ad M=H 0.3 N.T. 5.1 N.T. .5

Test animals receive an intraperitoneal injection of Run 20 0.2 0.5 ml. of 1:100 dilution of heparinized heart's blood gi '0 NT with a minimum of 90 percent parasitized cells (4 X 10 0,5 I I NT. 2.7 NJ. 9.7 cells), drawn from donor mice infected one week earlier with Plasmodium bergei. The donor strain is main- 3" 4 2, 6.6 9.8 tained by weekly passages in separate groups of mice -T-= noltested atlhis rate inoculated with a 0.5 ml. of 1:500 dilution of Preparation of Ethyl 3-Aminoadamantane-l-carboxyheparinized heart's blood. late 3-Aminoadamantane-1-carboxylic acid hydrochloride is described in South African patents 65/4921 and 66/0344. A mixture of this compound (10 g.) and thionyl chloride (125 ml.) was heated under reflux for about two hours. The resulting solution was cooled and extracted three times with benzene. The benzene solution thus obtained was dried over anhydrous sodium sulfate, was filtered and evaporated to dryness under vacuum. The product was identified as 3-amino-l-chloroformyl-adamantane hydrochloride by infrared spectrum.

The acid chloride hydrochloride thus obtained was suspended in dry benzene (150 ml.); ethanol (60 ml.) was added slowly at room temperature. The resulting reaction solution was stirred overnight. The solids were then separated and recrystallized from ethanol to give ethyl 3-aminoadamantanel -carboxylate hydrochloride m.p. 194-l96 C.

Analysis calculated for C H CINO Theory: C, 60.10; H, 8.53; N, 5.39;

Found: C, 59.83; H, 8.45; N, 5.16 This hydrochloride salt was dissolved in chloroform and was washed twice with saturated sodium bicarbonate solution and once with water; the chloroform solution was then dried over anhydrous sodium sulfate, was filtered and evaporated to dryness under vacuum to give ethyl B-aminOadamantane-l-carboxylate, which was used directly in the preparation described in Example 2.

I claim:

1. The compounds of the formula:

wherein R is located at either the 6- or 7 -position and 1. when R is at the 6-position,

a. l-adamantylamino or b. Z-adamantylamino; or,

2. when R is at the 7-position a. l-adamantylamino,

b. 2adamantylamin0,

c. 3,5,7-tri (R )-l-adamantylamino wherein each R independently represents 1. hydrogen, 2. methyl, or 3. ethyl,

subject to the limitation that all R groups together contain from one to five, both inclusive, carbon atoms; or

d. a 3-substituted-l-adamantylamino wherein the substituent at position 3 is carboxyl,

. loweralkoxycarbonyl, carbamoyl,

. loweralkylcarbamoyl,

. diloweralkylcarbamoyl,

. aminomethyl,

. loweralkylaminomethyl, or

. diloweralkylaminomethyl;

the moieties lower-alkyl" designating alkyl and alkoxy radicals of from one to three, both inclusive, carbon atoms; and the acid-addition salts thereof.

2. The compound of claim 1 which is 4-(1-adamantylamino)-7-chloroquinoline hydrochloride.

3. The compound of claim 1 which is 4-(l-adamantylamino-6-methoxyquinoline.

4. The compound of claim 1 which is 7-chloro-4-(3- ethoxycarbonyl-l-adamantylamino)quinoline hydrochloride.

5. The compound of claim 1 which is 4-(2-adamantylamino )-7-chloroquinoline hydrochloride.

6. The compound of claim 1 which is 7-chloro-4-[3- (N,N-diethylaminomethyl)-l-adamantylamino]quinoline hydrochloride.

7. The compound of claim 1 which is 7-chloro-4- (3,5,7-trimethyl-1-adamantylamino)quinoline hydrochloride.

8. The compound of claim 1 which is 7-chloro-4-[3- (N,N-diethylcarbamoyl)-l-adamantylamino]quinoline hydrochloride.

9. The compound of claim 1 which is 4-(3-carboxy-l -adamantylamino)-7-chloroquinoline hydrochloride. 

2. loweralkoxy; and wherein R1 represents,
 2. The compound of claim 1 which is 4-(1-adamantylamino)-7-chloroquinoline hydrochloride.
 2. loweralkoxycarbonyl,
 2. methyl, or
 2. when R is at the 7-position, a. 1-adamantylamino, b. 2-adamantylamino, c. 3,5,7-tri (R2)-1-adamantylamino wherein each R2 independently represents
 3. ethyl, subject to the limitation that all R2 groups together contain from one to five, both inclusive, carbon atoms; or d. a 3-substituted-1-adamantylamino wherein the substituent at position 3 is
 3. The compound of claim 1 which is 4-(1-adamantylamino-6-methoxyquinoline.
 3. carbamoyl,
 4. The compound of claim 1 which is 7-chloro-4-(3-ethoxycarbonyl-1-aDamantylamino)quinoline hydrochloride.
 4. loweralkylcarbamoyl,
 5. diloweralkylcarbamoyl,
 5. The compound of claim 1 which is 4-(2-adamantylamino)-7-chloroquinoline hydrochloride.
 6. The compound of claim 1 which is 7-chloro-4-(3-(N,N-diethylaminomethyl)-1-adamantylamino)quinoline hydrochloride.
 6. aminomethyl,
 7. loweralkylaminomethyl, or
 7. The compound of claim 1 which is 7-chloro-4-(3,5,7-trimethyl-1-adamantylamino)quinoline hydrochloride.
 8. The compound of claim 1 which is 7-chloro-4-(3-(N,N-diethylcarbamoyl)-1-adamantylamino)quinoline hydrochloride.
 8. diloweralkylaminomethyl; the moieties ''''loweralkyl'''' designating alkyl and alkoxy radicals of from one to three, both inclusive, carbon atoms; and the acid-addition salts thereof.
 9. The compound of claim 1 which is 4-(3-carboxy-1-adamantylamino)-7-chloroquinoline hydrochloride. 